Natural Killer T (NKT) cells have been implicated in the regulation of immune responses associated with a broad range of diseases, including autoimmunity, allergy, infectious disease and cancer. The study of the role of NKT cells in disease relies upon two similar but not equivalent mouse models, both of which have NKT cell deficiencies. In one model, the CD1d-encoding genes have been deleted, thereby preventing the development of any CD1d-reactive T cells, including, but not limited to, NKT cells. Another model directly targeted the TRAJ18 gene segment, which in combination with TRAV11 gene is absolutely required to form the NKT T cell receptor (TCR) with the appropriate antigenic specificity. Highlighting the importance of such mouse model, TRAJ18-deificient mice (J18-/-) have been cited in over 700 publications since their production in 1997. Using high-throughput sequencing, we recently made the observation that the J18-/- mouse has a significantly reduced conventional T cell repertoire in addition to a deficiency in NKT cells. As such, the NKT cell field urgently requires a new mouse model to permit the uninterrupted study of NKT cell biology. We propose to generate a new mouse strain in which the J18 gene segment will be specifically and uniquely modified to disrupt the generation of NKT cells without significantly altering the conventional T cell compartment using transcription activator-like effector nucleases (TALENs).